Extracellular Vesicles For Drug Delivery Research Articles

Extracellular Vesicles for Drug Delivery and Theranostics In Vivo.

Extracellular vesicles (EVs) are lipid bilayer-enclosed nanopouches generated by all cells and are abundant in various body fluids. Depending on the parent and recipient cells, EVs exchange diverse constituents including nucleic acids, proteins, carbohydrates, and metabolites. Morphologically, EVs suffer from low zeta potentials and short circulation times, but they also offer low intrinsic immunogenicity and inherent stability. Some crucial factors for the effective clinical application of EVs include controlling immune system clearance, achieving the large-scale production of EVs with efficient quality control, and determining the dominant mechanism of the in vivo action of EVs. In this Perspective, we shed light on how these intriguing nano-objects are utilized in cellular imaging and drug delivery for disease therapeutics. We also discuss potential strategies for overcoming the associated limitations.

Standardized Method to Functionalize Plasma-Extracellular Vesicles via Copper-Free Click Chemistry for Targeted Drug Delivery Strategies.

Extracellular vesicles (EVs) have emerged as potential vehicles for targeted drug delivery and diagnostic applications. However, achieving consistent and reliable functionalization of EV membranes remains a challenge. Copper-catalyzed click chemistry, commonly used for EV surface modification, poses limitations due to cytotoxicity and interference with biological systems. To overcome these limitations, we developed a standardized method for functionalizing an EV membrane via copper-free click chemistry. EVs derived from plasma hold immense potential as diagnostic and therapeutic agents. However, the isolation and functionalization of EVs from such a complex biofluid represent considerable challenges. We compared three different EV isolation methods to obtain an EV suspension with an optimal purity/yield ratio, and we identified sucrose cushion ultracentrifugation (sUC) as the ideal protocol. We then optimized the reaction conditions to successfully functionalize the plasma-EV surface through a copper-free click chemistry strategy with a fluorescently labeled azide, used as a proof-of-principle molecule. Click-EVs maintained their identity, size, and, more importantly, capacity to be efficiently taken up by responder tumor cells. Moreover, once internalized, click EVs partially followed the endosomal recycling route. The optimized reaction conditions and characterization techniques presented in this study offer a foundation for future investigations and applications of functionalized EVs in drug delivery, diagnostics, and therapeutics.

Engineered Extracellular Vesicles for Drug Delivery in Therapy of Stroke.

Extracellular vesicles (EVs) are promising therapeutic modalities for treating neurological conditions. EVs facilitate intercellular communication among brain cells under normal and abnormal physiological conditions. The potential capability of EVs to pass through the blood-brain barrier (BBB) makes them highly promising as nanocarrier contenders for managing stroke. EVs possess several potential advantages compared to existing drug-delivery vehicles. These advantages include their capacity to surpass natural barriers, target specific cells, and stability within the circulatory system. This review explores the trafficking and cellular uptake of EVs and evaluates recent findings in the field of EVs research. Additionally, an overview is provided of the techniques researchers utilize to bioengineer EVs for stroke therapy, new results on EV-BBB interactions, and the limitations and prospects of clinically using EVs for brain therapies. The primary objective of this study is to provide a comprehensive analysis of the advantages and challenges related to engineered EVs drug delivery, specifically focusing on their application in the treatment of stroke.

Characterization of Potent ABCG2 Inhibitor Derived from Chromone: From the Mechanism of Inhibition to Human Extracellular Vesicles for Drug Delivery.

Inhibition of ABC transporters is a promising approach to overcome multidrug resistance in cancer. Herein, we report the characterization of a potent ABCG2 inhibitor, namely, chromone 4a (C4a). Molecular docking and in vitro assays using ABCG2 and P-glycoprotein (P-gp) expressing membrane vesicles of insect cells revealed that C4a interacts with both transporters, while showing selectivity toward ABCG2 using cell-based transport assays. C4a inhibited the ABCG2-mediated efflux of different substrates and molecular dynamic simulations demonstrated that C4a binds in the Ko143-binding pocket. Liposomes and extracellular vesicles (EVs) of Giardia intestinalis and human blood were used to successfully bypass the poor water solubility and delivery of C4a as assessed by inhibition of the ABCG2 function. Human blood EVs also promoted delivery of the well-known P-gp inhibitor, elacridar. Here, for the first time, we demonstrated the potential use of plasma circulating EVs for drug delivery of hydrophobic drugs targeting membrane proteins.

Hybrid extracellular vesicles for drug delivery

Extracellular vesicles (EVs) are expected to serve as interesting drug delivery vectors as they may offer unique and new properties for drug delivery. Their natural origin, protein and nucleic acid composition, and intrinsic pleiotropic therapeutic effects could enable new possibilities in the field of drug delivery. Here, we aimed to review the methods used to produce Hybrid EVs, a recently emerged type of EV-based vector made from both EVs and synthetic vectors to exploit their respective properties. Hybrid EV/synthetic objects can be obtained by incubation, electrostatic interactions, polyethylene glycol (PEG)-mediated fusion, co-extrusion, freeze-thawing, or simple EV surface modification, leading to different types of objects. We also opted to review the properties of these vectors, and specifically compared them with those of other drug delivery vectors. It has to be noticed that only a limited number of study report loading metrics that allow cross article comparison. Based on this critical analysis, we attempted to draw the pith and marrow from these relatively difficult-to-compare studies and integrate them into the more general context of opportunities in drug delivery and drug development, with a particular focus on oncology.

Platelet-derived extracellular vesicles for drug delivery.

Platelet-derived extracellular vesicles (PEVs) are a subset of EVs that are released from platelets, which are small nuclear cell fragments that play a critical role in hemostasis and thrombosis. PEVs have been shown to have important roles in a variety of physiological and pathological processes, including inflammation, angiogenesis, and cancer. Recently, researchers, including our group have utilized PEVs as drug delivery platforms as PEVs could target inflammatory sites both passively and actively. This review summarizes the biological function of PEVs, introduces recent applications of PEVs in targeted drug delivery, and provides an outlook for the further development of utilizing PEVs for drug delivery.

Targeting Capabilities of Native and Bioengineered Extracellular Vesicles for Drug Delivery.

Extracellular vesicles (EVs) are highly promising as drug delivery vehicles due to their nanoscale size, stability and biocompatibility. EVs possess natural targeting abilities and are known to traverse long distances to reach their target cells. This long-range organotropism and the ability to penetrate hard-to-reach tissues, including the brain, have sparked interest in using EVs for the targeted delivery of pharmaceuticals. In addition, EVs can be readily harvested from an individual’s biofluids, making them especially suitable for personalized medicine applications. However, the targeting abilities of unmodified EVs have proven to be insufficient for clinical applications. Multiple attempts have been made to bioengineer EVs to fine-tune their on-target binding. Here, we summarize the current state of knowledge on the natural targeting abilities of native EVs. We also critically discuss the strategies to functionalize EV surfaces for superior long-distance targeting of specific tissues and cells. Finally, we review the challenges in achieving specific on-target binding of EV nanocarriers.

Chemically Modified Extracellular Vesicles and Applications in Radiolabeling and Drug Delivery.

Extracellular vesicles (EVs) have been exploited as bio-inspired drug delivery systems (DDS) in the biomedical field. EVs have more advantages than synthetic nanoparticles: they are naturally equipped to cross extra- and intra-cellular barriers. Furthermore, they can deliver functional biomolecules from one cell to another even far away in the body. These advantages, along with obtained promising in vivo results, clearly evidenced the potential of EVs in drug delivery. Nevertheless, due to the difficulties of finding a chemical approach that is coherent with EVs’ rational clinical therapeutic use, those in the drug delivery community are expecting more from EVs’ use. Therefore, this review gathered knowledge of the current chemical approaches dealing with the conjugation of EVs for drugs and radiotracers.

Separation, characterization, and standardization of extracellular vesicles for drug delivery applications.

Extracellular vesicles (EVs) are membranous nanovesicles secreted from living cells, shuttling macromolecules in intercellular communication and potentially possessing intrinsic therapeutic activity. Due to their stability, low immunogenicity, and inherent interaction with recipient cells, EVs also hold great promise as drug delivery vehicles. Indeed, they have been used to deliver nucleic acids, proteins, and small molecules in preclinical investigations. Furthermore, EV-based drugs have entered early clinical trials for cancer or neurodegenerative diseases. Despite their appeal as delivery vectors, however, EV-based drug delivery progress has been hampered by heterogeneity of sample types and methods as well as a persistent lack of standardization, validation, and comprehensive reporting. This review highlights specific requirements for EVs in drug delivery and describes the most pertinent approaches for separation and characterization. Despite residual uncertainties related to pharmacodynamics, pharmacokinetics, and potential off-target effects, clinical-grade, high-potency EV drugs might be achievable through GMP-compliant workflows in a highly standardized environment.

Extracellular Vesicles in HIV, Drug Abuse, and Drug Delivery.

Extracellular vesicles (EVs) are known to perform important biological functions and have been implicated in multiple disease pathogeneses, including HIV and drugs of abuse. EVs can carry biological molecules via biofluids such as plasma and cerebrospinal fluids (CSF) from healthy or disease organs to distant organs and deliver biomolecules to recipient cells that subsequently alter the physiology of the recipient organs. As biocarriers, EVs have the potential to be developed as non-invasive biomarkers for disease pathogenesis and drug abuse, as the level of specific EV components can be altered under disease/drug abuse conditions. Since many drugs don't cross the blood-brain barrier, EVs have shown the potential to encapsulate small drug molecules, including nucleotides, and carry these drugs to brain cells and enhance brain drug bioavailability. Through this special issue, we have covered several studies related to the role of EVs in altering biological functions via cell-cell interactions in healthy, HIV, and drug of abuse conditions. We have also included studies on the role of EVs as potential biomarkers for HIV pathogenesis and drugs of abuse. Further, the potential role of EVs in drug delivery in the CNS for diseases, including HIV-associated neurocognitive disorders and other neurological disorders, are covered in this issue.

Clinical Cancer Nanomedicine.

Nanotechnology offers new solutions for the development of cancer therapeutics that display improved efficacy and safety. Although several nanotherapeutics have received clinical approval, the most promising nanotechnology applications for patients still lie ahead. Nanoparticles display unique transport, biological, optical, magnetic, electronic, and thermal properties that are not apparent on the molecular or macroscale, and can be utilized for therapeutic purposes. These characteristics arise because nanoparticles are in the same size range as the wavelength of light and display large surface area to volume ratios. The large size of nanoparticles compared to conventional chemotherapeutic agents or biological macromolecule drugs also enables incorporation of several supportive components in addition to active pharmaceutical ingredients. These components can facilitate solubilization, protection from degradation, sustained release, immunoevasion, tissue penetration, imaging, targeting, and triggered activation. Nanoparticles are also processed differently in the body compared to conventional drugs. Specifically, nanoparticles display unique hemodynamic properties and biodistribution profiles. Notably, the interactions that occur at the bio-nano interface can be exploited for improved drug delivery. This review discusses successful clinically approved cancer nanodrugs as well as promising candidates in the pipeline. These nanotherapeutics are categorized according to whether they predominantly exploit multifunctionality, unique electromagnetic properties, or distinct transport characteristics in the body. Moreover, future directions in nanomedicine such as companion diagnostics, strategies for modifying the microenvironment, spatiotemporal nanoparticle transitions, and the use of extracellular vesicles for drug delivery are also explored.